Osteoporosis represents a major public health problem in the United States. Osteoporosis is associated with decreased systemic bone mineral density (BMD), an increased incidence of vertebrae, wrist and hip fractures, and tooth loss. The dominant pathogenic factor for osteoporosis in postmenopausal women is estrogen (E2) deficiency. In longitudinal NIH-supported clinical trials, we have shown accelerated alveolar crestal bone height and density loss in postmenopausal, E2- deficient women with a periodontitis history relative to E2-sufficient women, and in osteoporotic/osteopenic women versus women with normal lumbar spine BMD. Because of this relationship between E2- deficiency, osteoporosis and oral bone loss, it is desirable to test therapeutic strategies to mitigate alveolar bone loss in postmenopausal women. A recent discovery by Dr. Golub (Co-PI) showed that tetracyclines, including low-dose doxycycline (LDD), by virtue of a non- antimicrobial property, can: a) inhibit host-derived, tissue-destructive matrix metalloproteinases (MMPs), including collagenases, involved in bone resorption; and b) stimulate osteoblast activity and bone formation. These biological properties make tetracyclines compelling candidates for use in postmenopausal women with periodontitis. Therefore, the objective of this research is to investigate the therapeutic potential of LDD in postmenopausal osteopenia and periodontitis, diseases characterized by excess collagen breakdown and bone resorption. The hypothesis of this proposal is that LDD (compared to placebo) can improve radiographic, clinical and biochemical parameters of periodontitis in E2-deficient, osteopenic postmenopausal women with periodontitis. Accordingly, the specific aim of this proposal is to use a 2- year double-blind, placebo-controlled trial of E2-deficient women to determine the effect of LDD on: a) alveolar bone crestal and subcrestal density (measured by computer-assisted densitometric image analysis) and linear alveolar crestal bone height; b) clinical periodontal measurements such as probing depth and relative clinical attachment level; and c) gingival crevicular fluid markers of bone turnover (e.g., C- terminal telopeptide pyridinoline crosslinks [ICTP, a collagen breakdown fragment]). As a secondary aim, the study will evaluate the effect of LDD on systemic bone mineral density at the lumbar spine and femoral neck by dual-energy x-ray absorptiometry (DEXA) and the effect of LDD on serum and urine biochemical markers of bone turnover.